T<sub>H</sub>17 cells regulate chemokine expression in epithelial cells through C/EBPβ and dictate host sensitivity to colitis and cancer immunity.
basic_science · Level V
Where this comes from
- Record sourced from PubMed, PMID 40749055.
- Also identified by DOI 10.1126/sciadv.ads3530 and PMC identifier 12315988.
- Licence recorded as CC BY.
- The licence permits redistribution, so the abstract is shown in full and the full text is available from the publisher.
Abstract
T<sub>H</sub>17 cells play a critical role in inflammation, cancer development, and antitumor immunity in a context-dependent manner, but detailed mechanisms and their downstream signaling events remain poorly understood. Here, we describe that T<sub>H</sub>17 cytokines strongly inhibit expression of critical chemokines in epithelial tissues, which leads to blocking infiltration of proinflammatory immune cells into the colon, rendering resistance to DSS-induced colitis and colon cancer. We show that key chemokine expression dictates the sensitivity of WT mice to DSS treatment. Mechanistically, we identified C/EBPβ and STAT3 as negative regulators of key chemokine expression following IL-17 and IL-22 stimulation. Knockout of either C/EBPβ or STAT3 in mouse epithelial cells abolished the protective function of T<sub>H</sub>17 cytokines and converted resistant to sensitive phenotype. C/EBPβ ablation in cancer cells markedly enhanced chemokine expression, thus sensitizing cancer cells for anti-PD-1 immunotherapy. Overall, our findings have identified a previously unrecognized critical gap between T<sub>H</sub>17 cytokines, epithelial chemokine expression, and immune cell infiltration through a C/EBPβ-mediated pathway.
Medical subject headings
- CCAAT-Enhancer-Binding Protein-beta
- Th17 Cells
- Colitis
- Epithelial Cells
- Chemokines
- Colonic Neoplasms